Bioerodible polymers used to control the release of therapeutic agents physically dispersed in the polymer matrix have been described in a variety of contexts. One matrix which has been successful is a family of poly(ortho esters). These materials contain the pH-sensitive ortho ester linkage in their polymer backbone. Such polymers are described, for example, in U.S. Pat. No. 4,304,767 to Heller et al. Because the ortho ester linkages within these polymers are relatively stable at neutral pH, and hydrolyze progressively faster with the decreasing pH of the surrounding medium, the rate of erosion of the polymer can be manipulated within a very wide range by incorporating various levels and strengths of acidic excipients into the polymer matrix.
The method of preparing polymers according to the aforementioned patent comprises the addition of polyols to diketene acetals as shown in Scheme 1. ##STR1## Using this scheme, almost any diketene acetal and any diol can be used, and the synthetic method is thus extremely versatile. Polymers synthesized by this method are, however, not optimal for preparing soft or amorphous drug dosage forms such as bioerodible ointments, creams or gels due to the relatively rigid pentaerythritol segment in the polymer backbone.
Polymers and the method of preparing polymers for use in soft drug dosage forms are described in U.S. Pat. No. 5,030,457 to Ng et al. The method described in this patent involves reacting a monomeric ortho ester with a triol to form a polymer.
The polymers synthesized as described in U.S. Pat. No. 5,030,457 have the desirable properties of being able to undergo bioerosion and of being less rigid and more flexible and conforming than prior ortho ester polymers. Polymers synthesized by this method are, however, not optimal for preparing solid drug dosage forms.
There is thus a need in the art for a bioerodible composition which has a molecular structure of sufficient rigidity to enable its use as a bioerodible matrix in solid dosage forms such as pellets, capsules, suppositories or the like. An ideal material would enable the local or systemic delivery of an effective dose level of pharmaceutical agent from a subcutaneous pellet or the like at a desired rate for a period of time dictated only by clinical considerations and not by limitations of the solid dosage formulation. The ability to achieve this is particularly important with agents which when administered in an uncontrolled manner can produce serious side effects. The present invention provides bioerodible pellets, capsules, suppositories, etc., from which the release rate of the drug to be delivered--as well as the desired time period for drug delivery--can be carefully controlled. It provides materials which bioerode to small, water-soluble molecules that leave no residues in the tissue of the patient undergoing treatment. The invention thus enables improved treatment of a variety of disease states by the controlled delivery of drugs over prolonged periods of time.